Autoimmune (Type 1) diabetes (T1D) and autoimmune thyroid diseases (AITD) are the commonest autoimmune endocrine diseases. T1D and AITD are closely related, target-organ autoimmune diseases which are strongly associated with each other; i.e., both diseases frequently occur within the same family, and often in the same individual. Thus, we hypothesize that joint susceptibility genes for T1D and AITD play a major role in the etiology of these diseases, and the goals of our studies are to identify and characterize these genes. Our approach is to assemble and analyze a dataset of 200 families in which both T1D and AITD cluster together ("T1D-AITD families"). Our specific aims are: (1) To analyze, at the molecular level, the contribution of HLA class II genes to the joint susceptibility to T1D and AITD. We will sequence the DR and DQ genes in all T1D-AITD family members and examine how specific sequences affect the expression of T1D, AITD, or both. We will use computer-modeling studies to examine the influence of sequences identified on the structure of the peptide binding pocket. (2) To identify non-HLA susceptibility loci/genes for T1D-AITD by performing a whole genome scan on 200 T1D-AITD families. Loci showing significant LOD scores will be fine-mapped, and positional candidate genes will be identified and sequenced. Identified loci will also be analyzed for interactions with HLA class II genes. (3) To resolve genetic heterogeneity in the T1D-AITD families by identifying subsets of families which are most influenced by each of the loci identified in the genome scan. This will significantly amplify the power of the fine-mapping and gene identification at these loci (Specific Aim 2). We have the capacity and expertise to achieve these goals, expertise gained from our extensive studies on the genetics of AITD. In addition, we already have access to 100 T1D-AITD families, and we have results of preliminary analyses in 55 of them, which prove the efficacy of our approach. For recruiting appropriate families, we have established a consortium of 7 centers through which we will expand our dataset to include 200 families. Identifying susceptibility genes contributing to the common etiology of T1D and AITD will allow us to understand, at the most basic level, the common mechanisms that cause T1D and AITD, and possibly other autoimmune diseases. This will facilitate the development of novel treatment and prevention approaches based on the mechanisms initiating the diseases. [unreadable] [unreadable]